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R D Traub

Publications and source records attributed to R D Traub.

At least 55 records · Page 3Linked to original sources
PubMed1998

Electrical coupling underlies high-frequency oscillations in the hippocampus in vitro.

Coherent oscillations, in which ensembles of neurons fire in a repeated and synchronous manner, are thought to be important in higher brain functions. In the hippocampus, these discharges are categorized according to their frequency as theta (4-10Hz), gamma (20-80 Hz) and high-frequency (approximately 200 Hz) discharges, and they occur in relation to different behavioural states. The synaptic bases of theta and gamma rhythms have been extensively studied but the cellular bases for high-frequency oscillations are not understood. Here we report that high-frequency network oscillations are present in rat brain slices in vitro, occurring as a brief series of repetitive population spikes at 150-200 Hz in all hippocampal principal cell layers. Moreover, this synchronous activity is not mediated through the more commonly studied modes of chemical synaptic transmission, but is in fact a result of direct electrotonic coupling of neurons, most likely through gap-junctional connections. Thus high-frequency oscillations synchronize the activity of electrically coupled subsets of principal neurons within the well-documented synaptic network of the hippocampus.

Action Potentials↗
PubMed1998

Morphine disrupts long-range synchrony of gamma oscillations in hippocampal slices.

Oscillations in neuronal population activity within the gamma frequency band (>25 Hz) have been correlated with cognition: Gamma oscillations could bind together features of a sensory stimulus by generating synchrony between discrete cortical areas [Eckhorn, R., Bauer, R., Jordan, W., Brosch, M., Kruse, W., Munk, M. & Reitboeck, H. J. (1989) Biol. Cybern. 60, 121-130; Singer, W. & Gray, C. M. (1995) Annu. Rev. Neurosci. 18, 555-556]. Herein we demonstrate that morphine and beta-endorphin disrupt this long-range synchrony of gamma oscillations while leaving the synchrony of local oscillations relatively intact. The effect is caused by a decrease in type A gamma-aminobutyric acid receptor-mediated inhibition of both excitatory pyramidal cells and inhibitory interneurons. The effects of morphine on gamma oscillations were blocked by mu-opioid receptor antagonists but not by antagonists of delta or kappa receptors. Morphine also produced burst firing in interneurons, because synaptic excitation from pyramidal cells was no longer balanced by synchronous inhibitory postsynaptic potentials. The loss of synchrony of gamma oscillations induced by morphine may constitute one mechanism involved in producing the cognitive deficits that this drug causes clinically.

Analgesics, Opioid↗
PubMed1998

Gamma-frequency oscillations: a neuronal population phenomenon, regulated by synaptic and intrinsic cellular processes, and inducing synaptic plasticity.

Neurons are extraordinarily complicated devices, in which physical and chemical processes are intercoupled, in spatially non-uniform manner, over distances of millimeters or more, and over time scales of < 1 msec up to the lifetime of the animal. The fact that neuronal populations generating most brain activities of interest are very large-perhaps many millions of cells-makes the task of analysis seem hopeless. Yet, during at least some population activities, neuronal networks oscillate synchronously. The emergence of such oscillations generates precise temporal relationship between neuronal inputs and outputs, thus rendering tractable the analysis of network function at a cellular level. We illustrate this idea with a review of recent data and a network model of synchronized gamma frequency (> 20 Hz) oscillations in vitro, and discuss how these and other oscillations may relate to recent data on back-propagating, action potentials, dendritic Ca2+ transients, long-term potentiation and GABAA receptor-mediated synaptic potentials.

Animals↗
PubMed1998

'Dormant' inhibitory neurons: do they exist and what is their functional impact?

The concept of dormant interneurons is proving to be hard to define precisely. We argue here that the term is best used as an operational description of interneurons which are not lost from the epileptic brain, but which fail to perform adequately. We present evidence for the existence of functionally dormant interneurons in the tetanus toxin model of chronic epilepsy, and we explore the roles of a partial dormancy (and also of charge-screening) in the acute low magnesium model of epilepsy.

2-Amino-5-phosphonovalerate↗
PubMed1998

Disruption of synchronous gamma oscillations in the rat hippocampal slice: a common mechanism of anaesthetic drug action.

1. At the molecular level much progress has been made towards elucidating the mechanisms of action of general and dissociative anaesthetics. However, little is known about how these molecular actions may lead to disruption of cognitive function. 2. A promising physiological correlate of cognitive function is the ability of spatially separate areas of the brain to synchronize firing patterns via mutual inhibitory, gamma-frequency (20-80 Hz) electrical oscillations. Here we examine the effects of five different anaesthetic/hypnotic agents with different primary mechanisms of action on these oscillations in the hippocampus. 3. Gamma oscillations were elicited simultaneously at two sites at either end of area CAI by tetanic stimulation. Such oscillations are synchronous between these areas even when separated by up to c. 4 mm in control conditions. 4. Agents which act directly on GABA(A) receptor-mediated inhibition had different effects on synchronous gamma oscillations. Thiopental (10-200 microm) markedly disrupted the oscillation and resulting synchrony whereas the benzodiazepines diazepam and temazepam (0.05-1.0 microM) had little effect. 5. The opiate morphine (10-200 microM) and dissociative agent ketamine (10-100 microM) had a different profile of effects on gamma oscillations. However, as with thiopental, both agents markedly disrupted between site synchrony. These three agents demonstrated this effect at aqueous concentrations relevant to anaesthetic ED50. 6. Using the hippocampus as a model neuronal network we propose that, despite differing primary mechanisms of action, anaesthetics may disrupt cognitive function by interfering with the mechanism of generation of synchronous firing patterns between spatially separate areas of the brain.

Anesthetics↗
PubMed1998

Limbic gamma rhythms. I. Phase-locked oscillations in hippocampal CA1 and subiculum.

Gamma oscillations (approximately 40 Hz) were induced in transverse hippocampal slices by tetanic stimulation of CA1 and/or subiculum. Tetanic stimulation of each site elicited population gamma oscillations in the surrounding tissue <400 micro(m) away. Stimulation of CA1 alone could evoke activity at both CA1 and subiculum. Subicular stimulation, however, did not transmit to CA1. When the rostral end of CA1 was stimulated, gamma oscillations transmitted across <1.5 mm of silent CA1 before reappearing in the subiculum. Tetanic stimulation of CA1 increased [K+]o to 8.2 +/- 1.5 mM (mean +/- SE). The location of the peak increase corresponded to the site of local gamma generation. Silent areas of CA1 experienced smaller [K+]o increases, to 4.9 +/- 0.7 mM. The subiculum, which generated gamma, remained at the baseline 3.0 mM. Although fluctuations in [K+]o may have an impact on the generation of gamma rhythms, they are not necessary for them. Gamma oscillations had similar frequencies in CA1 and subiculum (40.4 +/- 2.9 and 43.9 +/- 3.1 Hz, respectively). When present in both, the oscillations typically were phase locked with the subiculum lagging by 5.4 +/- 1.8 ms. When both CA1 and subiculum were stimulated the lag decreased by 28%. These delays approximate those expected for the conduction velocity of axons between the two regions, here estimated at 0.52 +/- 0.07 m/s. Transmission of gamma oscillations from CA1 to subiculum was blocked by the focal addition of the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-receptor antagonist, 6-nitro-7-sulfamoylbenzo[f]quinoxaline-2,3-dione, to the subiculum. Oscillations induced in CA1 by local tetanic stimulation were blocked by focal application of the gamma-aminobutyric acid-A (GABAA) receptor antagonist, bicuculline, to CA1. Focal application of bicuculline to the subiculum blocked gamma due to subicular stimulation but not that due to CA1 stimulation. Bath-applied bicuculline disrupted subicular gamma evoked by subicular stimulation and led to a transient period of epileptiform responses before completely blocking responses. The further addition of the GABAB receptor antagonist, CGP 55845A, reversed this block, restoring the epileptic discharges evoked by tetanic stimulation. This suggests that the subiculum differs from hippocampal CA3 and neocortex, in having a powerful GABAB receptor-dependent mechanism to prevent epileptic discharges. The subiculum generates gamma rhythms both in response to local stimulation and to gamma rhythms evoked in CA1. Subicular gamma differs from that in CA1 in the presence of population spike doublets rather than singlets on many cycles. In both areas, generation of gamma by local stimulation depends on GABAA receptors, suggesting that the subiculum shares the interneuronal network mechanism we proposed for CA1.

Animals↗
PubMed1998

Limbic gamma rhythms. II. Synaptic and intrinsic mechanisms underlying spike doublets in oscillating subicular neurons.

Gamma oscillations were evoked in the subiculum in rat transverse hippocampal slices by tetanic stimulation (200 ms/100 Hz) of either CA1 or subiculum. Gamma oscillations in the subiculum differed from those in CA1 in containing population spike doublets as well as singlets. The present study addresses the origin of this more complex form of gamma oscillation in the subiculum. Intracellular recordings from subicular neurons revealed that 63% of them fired double action potentials on cycles of the gamma oscillation that generated population spike doublets after tetanic stimulation of either CA1 or subiculum. The remaining cells produced excitatory postsynaptic potentials (EPSPs), and occasional single spikes, on each cycle. Neurons that fired occasional single action potentials during gamma rhythms were "regular spiking" cells. They did not produce burst discharges during depolarizing steps, had minimal membrane potential sags on hyperpolarizing steps, and responded to single afferent volleys with a single action potential on an EPSP followed by a large inhibitory postsynaptic potential complex. Fast spiking cells were observed too infrequently to be studied in detail. Neurons that fired doublets during gamma rhythms were "intrinsic burst" (IB) cells. They generated bursts of action potentials on step membrane depolarizations, had significant membrane potential sags on step hyperpolarizations with an anodal break potential on return to rest, and fired multiple action potentials in response to high-intensity single afferent volleys. IB neurons did not fire action potential doublets during 1-s membrane depolarizations. Double action potentials, however, were evoked in these cells by depolarizing pulses at 40 Hz from hyperpolarized membrane potentials (-100 mV). Computer simulations suggest that the hyperpolarization between the depolarizations was essential for action potential doublets. The results in this and the previous paper suggest the following: either CA1 or subiculum alone can generate gamma oscillations gated by local networks of interneurons, oscillations in CA1 project through pyramidal cell axons to subiculum with a time lag expected from axon conduction delays, and oscillating sequences of EPSPs and intrinsic and/or synaptic hyperpolarizing potentials in IB subicular neurons generate gamma frequency spike doublets, which depend on both the intrinsic properties of these neurons and their temporally patterned synaptic input. This phenomenon could amplify gamma output from CA1 and modify its coupling to gamma oscillations in the wider limbic system.

Action Potentials↗
PubMed1997

Recurrent excitatory postsynaptic potentials induced by synchronized fast cortical oscillations.

Gamma frequency (about 20-70 Hz) oscillations occur during novel sensory stimulation, with tight synchrony over distances of at least 7 mm. Synchronization in the visual system has been proposed to reflect coactivation of different parts of the visual field by a single spatially extended object. We have shown that intracortical mechanisms, including spike doublet firing by interneurons, can account for tight long-range synchrony. Here we show that synchronous gamma oscillations in two sites also can cause long-lasting (>1 hr) potentiation of recurrent excitatory synapses. Synchronous oscillations lasting >400 ms in hippocampal area CA1 are associated with an increase in both excitatory postsynaptic potential (EPSP) amplitude and action potential afterhyperpolarization size. The resulting EPSPs stabilize and synchronize a prolonged beta frequency (about 10-25 Hz) oscillation. The changes in EPSP size are not expressed during non-oscillatory behavior but reappear during subsequent gamma-oscillatory events. We propose that oscillation-induced EPSPs serve as a substrate for memory, whose expression either enhances or blocks synchronization of spatially separated sites. This phenomenon thus provides a dynamical mechanism for storage and retrieval of stimulus-specific neuronal assemblies.

Animals↗
PubMed1997

Spatiotemporal patterns of gamma frequency oscillations tetanically induced in the rat hippocampal slice.

1. We used transverse and longitudinal rat hippocampal slices to study the synchronization of gamma frequency (> 20 Hz) oscillations, across distances of up to 4.5 mm. gamma oscillations were evoked in the CA1 region by tetanic stimulation at one or two sites simultaneously, and were associated with population spikes. Tetanic stimuli that were strong enough to induce oscillations were associated with depolarization of both pyramidal cells and interneurones, largely produced by activation of metabotropic glutamate receptors. 2. Computer simulations of gamma oscillations were also performed in a model with pyramidal cells and interneurones, arranged in a chain of five cell groups. This model had suggested previously that interneurone networks alone could generate synchronous gamma oscillations locally, but that pyramidal cell firing, by inducing spike doublets in interneurones, was necessary for the occurrence of highly correlated oscillations with small phase lag (< 2.5 ms), in a distributed network possessing long axon conduction delays. 3. In both experiment and model, pyramidal cell spikes occurred in phase with local population spikes, as did the first spike of the interneurone doublet. 4. The conductance of the interneurone alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor-mediated conductance was manipulated in the model, while the relation between oscillations at opposite ends of the chain was examined. When the conductance was large enough for doublet firing to be synaptically induced in interneurones, oscillation phase lags were < 2.25 ms across the chain. As predicted, experimental blockade of AMPA receptors resulted in increased phase lags between two sites oscillating simultaneously, compared with control conditions. 5. Both in model and in experiment, when stimuli to the two ends of the network were slightly different, cross-network synchronization occurred with a shorter phase lag at high frequencies than at lower frequencies. 6. These data suggest that, while interneurone networks alone can generate locally synchronized gamma oscillations, firing of pyramidal cells, and the synaptically induced doublet firing in interneurones, contribute to the stability and tight synchrony of the oscillations in distributed networks.

Action Potentials↗
PubMed1997

Simulation of gamma rhythms in networks of interneurons and pyramidal cells.

Networks of hippocampal interneurons, with pyramidal neurons pharmacologically disconnected, can generate gamma-frequency (20 Hz and above) oscillations. Experiments and models have shown how the network frequency depends on excitation of the interneurons, and on the parameters of GABAA-mediated IPSCs between the interneurons (conductance and time course). Here we use network simulations to investigate how pyramidal cells, connected to the interneurons and to each other through AMPA-type and/or NMDA-type glutamate receptors, might modify the interneuron network oscillation. With or without AMPA-receptor mediated excitation of the interneurons, the pyramidal cells and interneurons fired in phase during the gamma oscillation. Synaptic excitation of the interneurons by pyramidal cells caused them to fire spike doublets or short bursts at gamma frequencies, thereby slowing the population rhythm. Rhythmic synchronized IPSPs allowed the pyramidal cells to encode their mean excitation by their phase of firing relative to the population waves. Recurrent excitation between the pyramidal cells could modify the phase of firing relative to the population waves. Our model suggests that pools of synaptically interconnected inhibitory cells are sufficient to produce gamma frequency rhythms, but the network behavior can be modified by participation of pyramidal cells.

Electroencephalography↗
PubMed1996

A mechanism for generation of long-range synchronous fast oscillations in the cortex.

Synchronous neuronal oscillations in the 30-70 Hz range, known as gamma oscillations, occur in the cortex of many species. This synchronization can occur over large distances, and in some cases over multiple cortical areas and in both hemispheres; it has been proposed to underlie the binding of several features into a single perceptual entity. The mechanism by which coherent oscillations are generated remains unclear, because they often show zero or near-zero phase lags over long distances, whereas much greater phase lags would be expected from the slow speed of axonal conduction. We have previously shown that interneuron networks alone can generate gamma oscillations; here we propose a simple model to explain how an interconnected chain of such networks can generate coherent oscillations. The model incorporates known properties of excitatory pyramidal cells and inhibitory interneurons; it predicts that when excitation of interneurons reaches a level sufficient to induce pairs of spikes in rapid succession (spike doublets), the network will generate gamma oscillations that are synchronized on a millisecond time-scale from one end of the chain to the other. We show that in rat hippocampal slices interneurons do indeed fire spike doublets under conditions in which gamma oscillations are synchronized over several millimetres, whereas they fire single spikes under other conditions. Thus, known properties of neurons and local synaptic circuits can account for tightly synchronized oscillations in large neuronal ensembles.

Action Potentials↗
PubMed1996

Analysis of gamma rhythms in the rat hippocampus in vitro and in vivo.

1. We have shown previously, with experimental and computer models, how a '40 Hz' (gamma) oscillation can arise in networks of hippocampal interneurones, involving mutual GABAA-mediated synaptic inhibition and a source of tonic excitatory input. Here, we explore implications of this model for some hippocampal network phenomena in the rat in vitro and in vivo. 2. A model network was constructed of 1024 CA3 pyramidal cells and 256 interneurones. AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid), NMDA (N-methyl-D-aspartate), GABAA and GABAB receptors were simulated on pyramidal cells and on interneurones. 3. In both model and experiment, the frequency of network oscillations, in the gamma range, depended upon three parameters: GABAA conductance and decay time constant in interneurone-->interneurone connections, and the driving current to the interneurones. 4. The model of gamma rhythm predicts an average zero phase lag between firing of pyramidal cells and interneurones, as observed in the rat hippocampus in vivo. The model also reproduces a gamma rhythm whose frequency changes with time, at theta frequency (about 5 Hz). This occurs when there is 5 Hz modulation of a tonic signal to chandelier and basket cells. 5. Synchronized bursts can be produced in the model by several means, including partial blockade of GABAA receptors or of AMPA receptors on interneurones, or by augmenting AMPA-mediated EPSCs. In all of these cases, the burst can be followed by a 'tail' of transiently occurring gamma waves, a phenomenon observed in the hippocampus in vivo following sharp waves. This tail occurs in the model because of delayed excitation of the interneurones by the synchronized burst. A tail of gamma activity was found after synchronized epileptiform bursts both in the hippocampal slice (CA3 region) and in vivo. 6. Our data suggest that gamma-frequency EEG activity arises in the hippocampus when pools of interneurones receive a tonic or slowly varying excitation. The frequency of the oscillation depends upon the strength of this excitation and on the parameters regulating the inhibitory coupling between the interneurones. The interneurone network output is then imposed upon pyramidal neurones in the form of rhythmic synchronized IPSPs.

Action Potentials↗
PubMed1996

Neuronal networks for induced '40 Hz' rhythms.

A fast, coherent EEG rhythm, called a gamma or a '40 Hz' rhythm, has been implicated both in higher brain functions, such as the 'binding' of features that are detected by sensory cortices into perceived objects, and in lower level processes, such as the phase coding of neuronal activity. Computer simulations of several parts of the brain suggest that gamma rhythms can be generated by pools of excitatory neurones, networks of inhibitory neurones, or networks of both excitatory and inhibitory neurones. The strongest experimental evidence for rhythm generators has been shown for: (1) neocortical and thalamic neurones that are intrinsic '40 Hz' oscillators, although synchrony still requires network mechanisms; and (2) hippocampal and neocortical networks of mutually inhibitory interneurones that generate collective 40 Hz rhythms when excited tonically.

Animals↗
PubMed1996

Effects of intravenous anaesthetic agents on fast inhibitory oscillations in the rat hippocampus in vitro.

1. General anaesthetic agents prevent awareness of sensory input and subsequent recall of sensory events after administration. The mechanisms involved in higher sensory processing, including awareness and recall, are not fully elucidated. However, fast oscillations in neuronal activity in the 20-80 Hz (gamma) range have been strongly implicated. Here we have investigated the effects of two anaesthetic agents and a sedative/hypnotic drug on these oscillations. 2. Trains of fast oscillations, shown previously to be shaped by gamma-aminobutyric acid (GABAA) receptor activation, were evoked by pressure ejection of L-glutamate (10 nM) onto the perisomatic region of hippocampal area CAI in the presence of 3-((R)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (R-CPP), 50 microM, 6-nitro-7-sulphamoylbenzo[f]quinoxaline-2,3-dione (NBQX), 50 microM and 2-hydroxysaclofen, 0.2 mM. 3. Thiopentone (10-200 microM) and propofol (0.5-10 microM) dose-dependently decreased both the maximum oscillation frequency, by approx. 90%, and the incidence of evoked rhythmic oscillations by approx. 60%. Diazepam (0.05-1 microM) decreased maximum oscillation frequency by about 40% but did not affect the incidence of evoked oscillations. 4. The similar effects of thiopentone and propofol were mediated by both a large (about 600%) increase in the decay constant (tau D) of GABAA receptor-mediated inhibitory postsynaptic currents (i.p.s.cs) and a bicuculline-sensitive leak current. The two drugs had differing effects on i.p.s.c. amplitude. Diazepam caused a small increase in tau D (about 170%) and did not alter leak currents at the doses used. 5. Effects of the anaesthetic agents were seen on the above measurements at similar concentrations to those estimated in the CNS during clinical and veterinary anaesthesia. We suggest that the effects on fast oscillations associated with cognition may contribute to the mechanism by which these agents produce general anaesthesia.

Anesthetics↗
PubMed1996

On the structure of ictal events in vitro.

PURPOSE: To analyze the cellular and network mechanisms of sustained seizures, we reviewed the literature and present new data on in vitro epileptiform events. We considered single and recurring synchronized population bursts occurring on a time scale from tens of milliseconds to 1 min. METHODS: We used intracellular and field potential recordings, together with computer network simulations, derived from three types of experimental epileptogenesis: gamma-aminobutyric-acidA (GABAA) blockade, low extracellular [Mg2+]o, and 4-aminopyridine (4-AP). RESULTS: In all three models, sustained depolarizing synaptic currents developed, either through N-methyl-D-aspartate (NMDA) receptors, depolarizing GABAA receptors, or both. Ectopic action potentials (APs), probably originating in axonal structures, occurred in 4-AP and (as shown by other researchers) after tetanic stimulation; ectopic APs, occurring at sufficient frequency, should also depolarize dendrites, by synaptic excitation, enough to trigger bursts. CONCLUSIONS: Ictal-like events appear to arise from two basic mechanisms. The first mechanism consists of sustained dendritic depolarization driving a series of dendritic bursts. The second mechanism consists of an increase in axonal and presynaptic terminal excitability driving a series of bursts analogous to interictal spikes.

4-Aminopyridine↗
PubMed1995

Cellular mechanisms of 4-aminopyridine-induced synchronized after-discharges in the rat hippocampal slice.

1. We constructed a model of the in vitro rodent CA3 region with 128 pyramidal neurones and twenty-four inhibitory neurones. The model was used to analyse synchronized firing induced in the rat hippocampal slice by 4-aminopyridine (4-AP), a problem simultaneously studied in experiments in rat hippocampal slices. N-methyl-D-aspartate (NMDA) receptors were blocked. 2. Consistent with a known action of 4-AP, unitary EPSCs were assumed to be large and prolonged. With augmented EPSCs, spontaneous synchronized bursts occurred in the model if random ectopic axonal spikes were present. We observed probable antidromic spikes and miniature spikes experimentally. 3. Consistent with experiment, model synchronized bursts were preceded by a period of about 100 ms of increased unit activity and cell depolarization. In the model, this was caused in part by EPSPs consequent to ectopic axonal spikes. 4. After widespread firing had begun, full-blown synchrony in the model required orthodromic EPSPs. A single synchronized burst, once initiated, could proceed without further ectopic activity. 5. A depolarizing change in reversal potential for dendritic GABAA favoured the occurrence of synchronized after-discharges in the model. Consistent with this, bicuculline was found to block after-discharges in slices bathed in 4-AP (70 microM) during NMDA blockade. 6. These data indicate that, even with synaptic inhibition present, ectopic spikes can 'set the stage' for synchronized activity by depolarizing pyramidal cell dendrites, but that recurrent orthodromic EPSPs are required for expression of this synchrony. When synaptic inhibition is present, EPSCs may need to be larger than usual for synchrony to take place. Secondary bursts in 4-AP appear to be driven in part by a depolarizing GABAA-mediated current.

4-Aminopyridine↗
PubMed1995

Erosion of inhibition contributes to the progression of low magnesium bursts in rat hippocampal slices.

1. Bathing slices of rat hippocampus in media containing no magnesium ions results in epileptic discharges that originate in hippocampal area CA3. These discharges increase in severity gradually over periods of hours. 2. The progression of epileptic activity was much slower than the equilibration of extracellular magnesium activity and the resulting increase in strength of monosynaptic NMDA receptor-mediated excitation. Its time course matched that of a progressive decrease in pharmacologically isolated, evoked GABAA receptor-mediated inhibitory postsynaptic current (IPSC) in the CA3 pyramidal cells. Conductance decreased to 37 +/- 6% of control values after 4 h. Responses to exogenous GABA application decreased to 52 +/- 12%. 3. Maximal IPSC conductance in 0 mM extracellular Mg2+ ([Mg2+]o) also decreased gradually when epileptic activity was abolished by bath application of 20 microM 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) and 50 microM D-2-amino-5-phosphonovaleric acid (D-APV) throughout the 4 h incubation period. It reached 61 +/- 8% of control values, a significantly smaller decline than that seen after 4 h of epileptic activity. 4. The decrease in mean IPSC conductance only partially reversed when the recording electrode contained 100 mM Mg2+. Complete recovery of IPSC strength occurred when electrodes also contained either 50 mM MgATP or 20 mM BAPTA. Reintroduction of 1 mM [Mg2+]o rapidly abolished epileptic activity and caused a slow, partial increase in IPSC conductance. 5. In the presence of 1 mM [Mg2+]o, GABAA receptor-mediated inhibition had to decrease to 17 +/- 11% of control values, in the presence of 4-7 microM bicuculline, to reach threshold for epileptic activity. 6. These data demonstrate a postsynaptic decrease in GABAA receptor-mediated inhibition in the in vitro low magnesium model of epilepsy. We propose that the apparent leaching of intracellular Mg2+ ([Mg2+]i) from cells leads to loss of ATP and consequent partial dephosphorylation of the GABAA receptor and that this is exacerbated by epileptic activity.

Animals↗